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Crystal Structure of the Emerging Cancer Target MTHFD2 in Complex with a Substrate-Based Inhibitor
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2017 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 77, no 4, 937-948 p.Article in journal (Refereed) Published
Abstract [en]

To sustain their proliferation, cancer cells become dependent on one-carbon metabolism to support purine and thymidylate synthesis. Indeed, one of the most highly upregulated enzymes during neoplastic transformation is MTHFD2, a mitochondrial methylenetetrahydrofolate dehydrogenase and cyclohydrolase involved in one-carbon metabolism. Because MTHFD2 is expressed normally only during embryonic development, it offers a disease-selective therapeutic target for eradicating cancer cells while sparing healthy cells. Here we report the synthesis and preclinical characterization of the first inhibitor of human MTHFD2. We also disclose the first crystal structure of MTHFD2 in complex with a substrate-based inhibitor and the enzyme cofactors NAD(+) and inorganic phosphate. Our work provides a rationale for continued development of a structural framework for the generation of potent and selective MTHFD2 inhibitors for cancer treatment.

Place, publisher, year, edition, pages
AMER ASSOC CANCER RESEARCH , 2017. Vol. 77, no 4, 937-948 p.
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:kth:diva-204691DOI: 10.1158/0008-5472.CAN-16-1476ISI: 000393887800014PubMedID: 27899380Scopus ID: 2-s2.0-85014104419OAI: oai:DiVA.org:kth-204691DiVA: diva2:1105127
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceSwedish Research CouncilKnut and Alice Wallenberg FoundationWenner-Gren FoundationsTorsten Söderbergs stiftelseRagnar Söderbergs stiftelseSwedish Childhood Cancer FoundationSwedish Society for Medical Research (SSMF)Swedish Cancer SocietyÅke Wiberg Foundation
Note

QC 20170602

Available from: 2017-06-02 Created: 2017-06-02 Last updated: 2017-06-02Bibliographically approved

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CiteExportLink to record
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